2&#39;, 2&#39;-bistrifluoromethyloxetano(3&#39;, 4&#39;; 16alpha, 17alpha)derivatives of the pregnane series



United States Patent This invention relates to novelcyclopentanophenanthrene derivatives and to a process for the productionthereof. More specifically, this invention relates to novel2,2-bistrifiuoromethyloxetano (3 ',4';16oz,17oc) derivatives of thepregnane series.

The novel compounds of the present invention are represented by thefollowing formulas:

CH3 I 5:0

..0 R2 l l-OF;

CH2OR wherein R is hydrogen, chloro, fluoro or methyl;

R is hydrogen or methyl;

R is keto or the group in which R is hydrogen, tetrahydropyran-Z-yl,tetrahydrofuran-2-yl or a hydrocarbon carboxylic acyl group of less than12 carbon atoms; R being keto when Z is the carbon-carbon double bond;

R is hydrogen, phosphono, tetrahydropyran-Z-yl, tetrahydrofuran-Z-yl ora hydrocarbon carboxylic acyl group of less than 12 carbon atoms;

R is hydrogen or fluoro; and

each of Z and Z is a carbon-carbon single bond or a carbon-carbon doublebond, 2' being a carbon-carbon single bond when R is hydrogen.

The hydrocarbon carboxylic acyl and acyloxy groups of the presentinvention will contain less than 12 carbon atoms and may be of astraight, branched, cyclic or cyclicaliphatic chain structure. Thisstructure may be saturated, unsaturated, or aromatic and optionallysubstituted by functional groups such as hydroxy, acyloxy containing upto 12 carbon atoms, nitro, amino, halogeno, and the like. Typical estersthus include acetate, propionate, enanthate, benzoate, trimethylacetate,t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate,,B-chloropropionate, adamantoate, and the like.

The phosphono group includes the mono or di-sodium or potassium saltsthereof.

The novel compounds of the present invention as repice resented byFormula A are progestational agents and are useful in fertility controland the management of various menstrual disorders. The novel compoundsas represented by Formula B are cortical hormones with highantiinfiammatory and low catabolic activities and are useful in thetreatment of rheumatoid arthritis, contact dermatitis, allergies and thelike. The compounds of the present invention may be administered viausual routes in the standard pharmaceutical compositions and at dosagesappropriate for the particular condition being treated.

The compounds of the present invention are prepared in the followingway.

The starting material is a 3,20-diketo-A -diene of the pregnane seriesand may optional-1y contain a 6-chloro, fluoro or methyl group, a9a-fluoro group, an llfl-hydroxy group, and a 21-acetoxy group.

In the practice of the process, a 3-keto-A -ene group in the startingmaterial is protected by formation of an ethylene ketal as for example,by treatmentwith Z-methyl-Z- ethyl-1,3-dioxolane and p-toluenesulfonicacid to form a 3,3-ethylenedioxy group. With the protecting groupintact, the compound in an inert organic solvent such as benzene,dioxane and the like, is irradiated with ultraviolet light of a wavelength in the range of about 270 to about 330 m while bubblinghexafluoroacetone through the solution. of these solvents, benzene isthe preferred choice. Under these conditions, the hexafiuoroacetone addsacross the A -dou-ble bond to afford the novel compounds,2',2-bistrifluoromethy-loxetano 3 ',4';l6ot,17zx.) derivatives of thepresent invention. The orientation of the oxetano group with respect tothe steroid nucleus is predominantly alpha. The reaction is usuallycomplete within a period of one hour but in any event, its progress canbe readily followed by observing the U.V. spectra of the reactionmixture.

Subsequent to the photochemical addition, the protecting ethylene ketalgroup at the 3-position is removed by hydrolysis under acidicconditions, such as with p-toluenesulfonic acid in acetone. The21-acetoxy group is converted to a 2l-hydroxy group by alkalinehydrolysis such as with potassium carbonate in methanol.

The 21-hydroxy derivatives are treated with methanesulfonyl chloride,and subsequently with sodium iodide, to afford a 21-iodo intermediate.This inter-mediate is allowed to react with silver mono-basic phosphatein acetonitrile to yield the 2l-phosphate compounds of the presentinvention. Alternatively, treatment of the 21-hydroxy compound withdihydropyran or dihydrofuran in the presence of an acidic catalyst suchas p-toluenesulfonic acid or with a hydrocarbon carboxylic acidanhydride in the presence of pyridine leads to the formation of a2l-tetrahydropyran-Z-yl, a 2l-tetrahydrofuran-2-yl or 2l-acylderivatives, respectively. 7

Optionally, a A -diene, a M' -diene or a A -trien system may beintroduced into the steroid nucleus subsequent to the photochemicaladdition of hexafluoroacetone. Thus, treatment of a 3-keto A -ene with2,3-dichloro-5,6- dicyanobenzoquinone affords the A -diene system.Alternatively, treatment of the 3-keto-A -ene with chloranil in xyleneaffords the M' -diene system. Treatment of the A diene with chloranil inn-a my-l alcohol affords the A triene system.

Selective reduction of a 3-keto-A '-ene or a 3-keto-A diene as forexample, by treatment with sodium borohydride in isopropanol, andsubsequent treatment with di-' hydropyran, dihydrofuran or with ahydrocarbon carboxylic acid anhydride, afford the corresponding3fi-(tetrahydropyran-Z-yloxy) 3 8 (tetrahydrofuran-Z-yloxy) or3fl-acyloxy compounds of the present invention.

The following examples are set forth to illustrate but are not intendedto limit the scope of the present invention.

3 PREPARATION A To a suspension of 1 g. of 9rx-fiL10r0-1 113,170t-dihYd1'0XY- 21-acetoxypregn-4-ene-3,ZOO-dione in 27 ml. ofmethanol and 1 ml. of water, under nitrogen is added 1.4 g. ofsemicarbazide hydrochloride and 0.74 g. of sodium bicarbondate. Themixture is heated at reflux for three hours and then at 45 C. for hours.The suspension is cooled and 36 ml. of water are slowly added. The solidis collected by filtration, washed with water and dried to yield 900fluoro-l1 8,17u-dihydroxy-21-acetoxypreg-4-ene-3,20- bis-semicarbazonewhich is recrystallized from pyridine: methanol.

A solution of 1 g. of the latter material in 20 ml. of acetic acid and 1ml. of acetic anhydride is heated at reflux under nitrogen for 1 hour.The reaction mixture is then concentrated under reduced pressure to avolume of about 12 ml..and treated with 6 ml. of water and 3 ml. ofpyruvic acid. The mixture is allowed to stand at room temperature for 40hours and at 60 C. for 2 hours and is then diluted with water andextracted with chloroform. These extracts are washed with water, dilutepotassium bicarbonate solution and water, dried over mangesium sulfateand evaporated to dryness under reduced pressure. The residue ischromatographed on neutral alumina with benzene to yield9a-fiuoro-11B-hydroxy-2l-acetoxypregna- 4,16-diene-3,20-dione which maybe recrystallized from acetone :ether.

Utilizing the same procedure, the following compounds, namely:

6u-Chl0l'O-1 7a-hydroxypregn-4-ene-3 ,20-dione;

6a-fluoro-17a-hydroxy-19-norpregn-4-ene-3,20-dione;

6a-methyl-17a-hydroxypregn-4-ene-3 ,ZO-dione;

6a-methyl-17a-hydroxy-19-norpregn-4-ene-3 ,ZO-dione;

1-7u-hydroxy-19-norpregn-4-ene-3,ZO-dione;

6a-fiuoro-17a-hydroxypregn-4-ene-3,ZO-dione;

1 1 8, 17adihydr0xy-2 1 -acetoxypregn-4-ene-3,20-dione;

6a-methyl-9wfluoro-1 113, 17ut-dihydroxy-2 1-acetoxypregn-4-ene-3,20-dione;

6a-methyl-1 119,17a-dihydroxy-2l-acetoxy-pregn- 4-ene-3 ,20-dione;

6u-methyl-1 lfl,17a-dihydroxy-21-acetoxypregn-4- ene-3,20-dione;

6a-fluoro-1 15, 17a-dihydroxy-21-acetoxypregn-4- ene-3 ,ZO-dione;

6a-ChlO10-1 7u-hydroxy-19-norpregn-4-ene-3 ,ZO-dione;

9a-fluoro-1 15,17a-dihydroxy-21-acetoxypregn-4-ene- 3 ,ZO-dione; and

6a-chloro-115,17a-dihydroxy-21-acetoxypregn-4- ene-3 ,ZO-dione;

are converted to the 3,20-diketo-A compounds used as starting materialsfor the present invention; namely:

6a-chloropregna-4,16-diene-3,20-dione;

6wfiuoro-19-norpregna-4,16-diene-3,20-dione;

6a-methylpregna-4,16-diene-3 ,20-dione;

Got-methyl-19-norpregna-4,16-diene-3,20-dione;

19-norpregna-4,16-diene-3,20-dione;

6a-fluoropregna-4,16-diene-3 ,20-dione;

1 1,8-hydroxy-21-acetoxypregna-4,16-diene-3,20-dione;

6a-methyl-9e-fluoro-11fl-hydroxy-21-acetoxy-pregna-4,16-diene-3,20-dione;

6a-methyl-1 lfi-hydroxy-Z1-acetoxypregna-4,1G-diene- 3,20-dione;

6u-chloro-19-norpregna-4,16-dienc-3,20-dione;

9u-fiuoro-1 lfl-hydroxy-Z1-acetoxypregna-4,16-diene- 3,20-dione; and

6a-chloro-1lfl-hydroxy-Zl-acetoxypregna-4,lG-diene- 3,20-dione.

Example 1 A mixture of 2 g. of l-dehydroprogesterone in '30 ml. of2-methyl-2-ethyl-1,3-dioxo1ane and 70 mg. of p-toluenesulfonic acid isheated at reflux with distillation for one hour. The mixture is thencooled, diluted with water and extracted with ethyl acetate. Theextracts are washed to neutrality, dried and evaporated to dryness toyield 3,3 ethylenedioxypregna-S,16-diene-3,20-dione which isrecrystallized from acetone-hexane.

A mixture of 2.0 g. of the above material in ml. of benzene isirradiated with a 70 watt Hanau high pressure mercury vapor lamp with aPyrex filter at room temperature while bubbling hexafluoroacetonethrough the solution. At the end of the reaction time, which may befollowed by observing the U.V. spectrum, the solvent is evaporated underreduced pressure and the reaction product is chromatographed on silicaeluting with ethyl acetatezbenzene to yield2,2'-bistrifluoromethyloxetano(3,4';16a,17a)-3,3-ethylenedioxypregn-S-en-ZO-one.

A mixture of 0.5 of the latter compound in 30 ml. of acetone and 50 mg.of p-toluenesulfonic acid is allowed to stand at room tempertaure for 15hours. It is then poured into ice Water and extracted with ethylacetate. These extracts are Washed with Water to neutrality, dried oversodium sulfate and evaporated to dryness. The residue is triturated withether to yield2,2'-bistrifiuoromethyloxetano(3',4;16m,17a)-pregn-4-ene-3,20-dionewhich is recrystallized from acetonezhexane.

Utilizing the same procedure, the following starting materials, namely;

6a-ch1oropregna-4,16-diene-3,20-dione;

6a-chloro-19-norpregna-4,16-diene-3,20-dione;

6a-methylpregn a-4, 16-diene-3 ,20'dione;

19-norpregna-4,16-diene-3 ,ZO-dione;

1lli-hydroxy-Z]-acetoxypregna-4,16-diene-3,20-dione;

9a-fluoro-1lfl-hydrdxy-Z1-acetoxypregna-4,16-diene-3,20-

dione;

6a-methyl-9 a-fiuoro-l 1 ,B-hydroxy-Z l -acetoxypregna-4,l 6-

diene-3 ,ZO-dione;

6rx-methyl-1 1fi-hydroxy-2l-acetoxypregnal,16-cliene- 3,20-dione;

6a-fiuoro-1 lfi-hydroxy-Zl-acetoxypregna-4,16-diene-3,20-

dione; and

are converted to the 2',2'-bistrifiuoromethyloxetano(3",4'; ;,17a)compounds of the present invention, namely:

fluoro-l lfl-hydroxy-Zl-acetoxypregn-4-ene-3,20 dione; respectively.

Example 2 A mixture of 1 g. of 2,2'-bistrifluoromethyloxetano(3', 4;16a,17a)-pregn-4-ene-3,20-dione, 2 g. of chloranil and ml. of xylene isrefluxed under an atmosphere of nitrogen for 16 hours. The mixture iscooled, washed with a cold 10% sodium hydroxide solution and then withwater, dried over sodium sulfate and evaporated under reduced pressure.The residue is chromatographed on neutral alumina and further purifiedthrough recrystallization from acetone:hexane to yield2,2-bistrifluoromethyloxetano(3',4';16a,17a)-pregna-4,6-diene-3,20-dione.

Utilizing the same procedure, the2',2-bistrifiuoromethy10xetano(3,4';16a,17u) compounds prepared as finalproducts in Example 1 are converted to the A compounds. Notably amongthese are the following:

2,2'-bistrifluoromethyloxetano(3 ',4';16oz,l7oz)-6-Ch1010-pregna-4,6-diene-3,20-dione; 2',2'-bistrifluoromethyloxetano 3',4';16uc,170)-6-ChlOIO- 19-norpregna-4,6-diene-3,20-dione;2,2'-bistrifluoromethyloxetano (3 ,4';16a,17a)-6-methylpregna-4,6-diene3,20-dione;2',2'-bistrifiuoromethyloxetano(3',4';16a, 17a) -6-methy1-19-norpregna-4,6-diene-3,20-dione; 2,2'-bistrifluoromethyloxetano( 3,4;16a,17a)-19-norpregna-4,6-diene-3,20-dione;2',2-bistrifluoromethyloxetano( 3 ',4';16oz,17a)6-fiu0r0pregna-4,6-diene-3,20-dione; 2,2-bistrifiuoromethyloxetano3',4';16ot,17a) -1 IB-hydroxy-21-acetoxypregna-4,6-diene-3,ZO-dione;2,2-bistrifluoromethyloxetano 3 ',4';160t,17oc)-90zfi11010-1lfi-hydroxy-Z1-acetoxypregna-4,6-diene-3,20-dione;2,2'-bistrifiuoromethyloxetano( 3 ',4';16a,17a) -6-methyl-9a-fluoro-11,8-hydroxy-21-acetoxypregna-4,6-diene- 3,20-dione;2,2-bistrifiuoromethyloxetano (3 ,4;16a,17a)-6-methyl- 1lfi-hydroxy-Z1-acetoxypregna-4,6-diene-3 ,20-dione2',2'-bistrifiuoromethyloxetano (3 ',4';1 6oz, 17a)-6-flll0r0-1LB-hydroxy-Z1-acetoxypregna-4,6-diene 3,20 dione; and2',2-bistrifiuoromethyloxetano 3 ',4';160t,17a)-6-9ot-di fluoro-1LB-hydroxy-Z1-acetoxypregna-4,6-diene 3,20- dione, respectively.

Example 3 A mixture of 0.5 g. of 2',2'-bistrifiuoromethyloxetano(34';16a,17a)-pregn-4-ene-3,20-dione, 10 ml. of dioxane and 0.35 g. of2,3-dichloro-5,6-dicyano-1,4-benzoquinone is refluxed for 10 hours. Themixture is then cooled, filtered and evaporated to dryness. The residueis dissolved in acetone and this solution is then filtered through 10 g.of alumina and concentrated to yield2,2'-bistrifluoromethyloxetano(3',4';16a,17a)-pregna 1,4 diene-3,20-dione which is further purified by recrystallization fromacetonezhexane.

Utilizing the same procedure, the following starting materials, namely:

6 1lfi-hydroxy-Z1-acetoxypregna-4-ene-3,20-dione; and2',2-bistrifluoromethyloxetano (3 ',4';16oz,17ot) -6ot,9u-

fluoro-l 1,8-hydroxy-2 1-acetoxypregna-4-ene- 3,20-dione;

are converted to the corresponding final products, namely Example 4 Asolution of 200 mg. of2',2'-bistrifluoromethyloxetano(3',4';16a,17a)-pregn-4-ene-3,20-dione in32 ml. of anhydrous isopropanol and 25 mg. of sodium borohydride isstirred at room temperature for 15 hours, One-hundred ml. of water areadded and the resulting suspension extracted several times with ether.The ether phase is dried over sodium sulfate and evaporated to drynessunder reduced pressure to yield 2',2-bistrifluoromethyloxetano(3',4;16u,17e)-3,8-hydroxypregn-4-en-20-one which may be further purified byrecrystallization from ether.

Two milliliters of dihydropyran are added to a solution of 1 g. of thelatter material in 15 ml. of benzene. About 1 ml. is removed bydistillation to remove moisture and 0.4 g. of p-toluenesulfonyl chlorideis added to the cooled solution. This mixture is allowed to stand atroom temperature for four days, and is then washed with aqueous sodiumcarbonate solution and water, dried and evaporated. The residue ischromatographed on neutral alumina, eluting with hexane, to yield2',2-bistrifluoromethyloxetan0(3,4;16a,17u)-3/8-(tetrahydropyran 2yloxy)- pregn-4-en-20-one which is recrystallized from pentane.

Utilizing the same procedure, the following starting materials, namelyare converted to the corresponding 3,8-(tetrahydropyran- 2-yloxy)compounds, namely:

2',2-bistrifiuoromethyloxetano 3 ',4;16a,17a)-3B-(tetrahydropyran-Z-yloxy) -6-chloropregna-4,6-diene- 3,20-dione;

2',2-bistrifiuoromethyloxetano 3',4;16a,17u)-3;3-(tetrahydropyran-Z-yloxy)-6-chloro-19-norpregna-4,6-diene-3,20-dione;

2',2'-bistrifiuoromethyloxetano (3 ',4';16ot,l70t)-3[3-(tetrahydropyran-Z-xyloxy -6a-methylpregn-4-ene-3 ,20- dione;

2',2'-bistrifl uoromethyloxetano 3 ',4';16a, 17a)-3,8-(tetrahydropyran-Z-yloxy -6-methylpregna-4,6-diene- 3 ,20-dione;

Utilizing the same procedure and starting materials, with one exception,namely substituting dihydrofuran in place of dihydropyran, there areobtained the corresponding 3B-(tetrahydrofuran-Z-yloxy) compounds.

Example A solution of 200 mg. of 2',2'-bistrifiuoromethyloxetano (3',4';16a,l7a)-6-chloropregna-4,6-diene-3,20-dione in 32 ml. of anhydrousisopropanol and 25 mg. of sodium borohydride is stirred at roomtemperature for hours. One hundred ml. of water is added and theresulting suspension extracted several times With ether. The ether phaseis dried over sodium sulfate and evaporated to dryness under reducedpressure to yield2,2-bistrifiuoromethyloxetano(3',4;l6a,17a)-3fl-hydroxy-6 chloropregna4,6- dien-ZO-one which may be further purified by recrystallization fromether.

A mixture of 1 g. of the above compound, 4 ml. of pyridine and 2 ml. ofacetic anhydride is allowed to stand at room temperature for 15 hours.The mixture is then poured into ice water and the solid which forms iscollected by filtration, Washed with water and dried to yield2,2'-bistrifiuoromethyloxetano(3',4';16oc,17a) 3,8acetoxy-6-chloropregna-4,6-dien-20-one which may be further purifiedthrough recrystallization from acetone: hexane.

Utilizing the same procedure and starting material, with one exception,namely substituting .propionic anhydride, caproic anhydride, enanthicanhydride and cyclopentylpropionic anhydride in place of aceticanhydride, there are obtained the corresponding 3 ,B-propionate,3g8-caproate, 3fl-enanthate, and 3B-cyclopentylpropionate compounds.

Example 6 A suspension of 1 g. of 2',2'-bistrifiuoromethyloxetano-(3',4-';16oc,17oc) 115 hydroxy 21 acetoxypregn-4-ene- 3,20-dione in 60ml. of methanol is treated with a solution of 1 g. of potassiumcarbonate in 6 ml. of Water. The mixture is heated at reflux for onehour, cooled in ice and diluted with water. The solid which forms iscollected by filtration, washed with water and dried to yield 2',2bistrifiuoromethyloxentano(3',4';16a,17a) 116,21-dihydroxypregn-4-ene-3,20-dione which is recrystallized fromacetonezhexane.

Two milliliters of dihydropyran are added to a solution of l g. of theabove material in 15 ml. of benzene. About 1 ml. is removed bydistillation to remove moisture and 0.4 g. of p-toluenesulfonic acid isadded to the cooled solution. This mixture is allowed to stand at roomtemperature for 4 days, and is then washed with aqueous sodium carbonatesolution and water, dried and evaporated. The residue is chromatographedon neutral alumina, eluting with hexane, to yield2,2-bistrifiuoromethyloxetano-(3',4';16a,1700-1IB-hydroxy-ZI(tetrahydropyran-2yloxy)-pregn-4-ene-3,20-dione which is recrystallizedfrom pentane.

Utilizing the same procedure, the following starting materials, namelyUtilizing the same procedure and starting material, with one exception,namely substituting dihydro'furan in place of dihydropyran, there areobtained the corresponding 21- (tetrahydrofuran-Z-yloxy) compounds.

Example 7 A suspension of 1 g. of '2,2'-bistrifluoromethyloxetano-(3',4';16m,17e)-6a,9a-difiuoro-1lB-hydroxy -21acetoxypregna-1,4-diene3,20 dione in 60 ml. of methanol is treated Witha solution of 1 g. of potassium carbonate in 6 ml. of water. The mixtureis heated at reflux for one hour, cooled in ice and diluted with water.The solid which forms is collected by filtration, washed with water anddried to yield 2',2 bistrifiuoromethyloxetano(3',4';

16a,17a)-6u-difiuoro-116,21 dihydroxypregna-1,4-diene- 3,20-dione whichis recrystallized from acetone:hex-ane.

A mixture of 1 g. of the above compound, 4 ml. of pyridine and 2 ml. ofpropionic anhydride is allowed to stand at room temperature for 15hours. The mixture is A mixture of 2 g. of 2',2'-bistrifiuoromethyloxetano (3',4';160c,170t)60c,90t difluoro115,21-dihydroxypregna- 1,4-diene-3,20-dione in 8 ml. of pyridine and 4ml. of trimethylacetyl chloride is headed at steam bath temperatures forone hour. The mixture is then poured into ice water. The solid whichforms is collected by filtration, washed with water and dried to yield2',2'-bistrifluoromethyloxetano(3',4';16a,17a) 6u,9adifluoro-115-hydroxy 21 trimethylacetoxypregna-1,4-diene-3,20-dionewhich may be recrystallized from methylene chlon'dezhexane.

In a similar fashion, other 21-hydroxy compounds prepared in Examples 6and 7, are converted to the corresponding ZI-trimethylacetoxy compounds.

Example 9 To a cooled solution C.) of 3.4 g. of2',2-bistrifluoromethyloxetano(3,4;16u,17a) 601,9 difluoro-115,21-dihydroxypregna 1,4 diene-3,20-dione in 20 ml. of 9:1chloroformzpyridine is added in small portions 1.4 g. of methanesulfonylchloride. The reaction mixture is allowed to stand for 14 hours at 0 C.and is then washed with dilute hydrochloric acid, water and sodiumbicarbonate solution. The chloroform is removed by evaporation underreduced pressure and the residue is dissolved in 20 ml. of acetonetreated at room temperature and under stirring with 4 g. of sodiumiodide. Sodium thiosulfate solution is added, followed by water. Thesolid is collected and dried to yield 2',2'-bistrifluoromethyloxetano(3',4';16a,17a)-6oc,9a-difiu0r0 115hydroxy-Zl-iodopregna-l,4-diene-3,20-dione. A mixture of 1 g. of theabove 21-iodo intermediate and 1.1 molar equivalents of silver monobasicphosphate in 60 m1. of acetonitrile is heated at reflux for 2 hours. Themixture is then filtered and evaporated to dryness of yield2,2'-bistrifluoromethyloxetano(3',4';l6a,17a) 604,90;difluoro-115-hydroxy-21-phosphatopregna 1,4 diene-3,20-dione which maybe crystallized from methanol ethyl acetate. This product, dissolved inmethanol, may be triturated with aqueous sodium hydroxide to yieldcorresponding monosodium and disodium salts. In a similar fashion,potassium hydroxide aflords the monopotassium and dipotassium salts.

In a similar fashion, other 21-hydroxy compounds of the presentinvention are converted to the corresponding 21-iodo intermediates andthen to the corresponding 21- phosphate compounds.

Example A mixture of 1 g. of 2',2-bistrifluoromethyloxetano(3',4;16u,17a)-pregna 4,6 diene3,20-dione, 2 g. of chloranil and 10 ml.of n-amyl alcohol are refluxed under nitrogen for 24 hours. The mixtureis then cooled, washed with a cold aqueous solution of 10% sodiumhydroxide until the washings were colorless, dried over sodium sulfateand evaporated. Chromatography of the residue on neutral alumina yields2',2' bistrifluoromethyloxetano (3',4'; 16a,17a)-pregna 1,4,6,triene-3,20-dione which may be further purified throughrecrystallization from acetonezhexane.

Utlizing the same procedure, other2',2'-bistrifluoromethyloxetano(3',4';l6a,17a) pregna 4,6 dienes areconverted to the corresponding A -trienes. Notably among these are thefollowing.-

2,2'-bistrifluoromethyloxetano(3',4';16a,l7a)-6-chloropregna-1,4,6-triene-3 ,20-dione; 2',2'-bistrifiuoromethyloxetano(3',4';16u,17a)-6- methylpregna-l,4,6-triene-3,20-dione; 2',2'bistrifluoromethyloxetano( 3',4';16u,17a)-6fluoropregna-1,4,6,-triene-3,20-dione;2',2-bistrifluoromethyloxetano(3',4';16a,17a)-6- methyl-115,21-dihydroxypregna-1,4,6,-triene- 3,20-dione;2',2'-bistrifluoromethyloxetano(3,4';16a,l7a)-6- methyl-9 a-fluoro-l15,21-dihydroxypregna- 1,4,6,-triene-3,20-dione;

fluoro-l 15,2l-dihydroxypregna-1,4,6,-trienedifluoro-l15,2l-dihydroxypregna-1,4,6,-trienemethyl-115-hydroxy-21-acetoxypregna-1,4,6,-

methyl-9'ot-fluoro- 1 15-hydroxy-2 l-acetoxypregna- 1,4,6,-triene-3,20-dione; 2',2'-bistrifiuoromethyloxetano(3,4;16a,17a)-6-fluoro-l 15-hydroxy-21-acetoxypregna-1,4,6,-

triene-3,20-dione; and2,2'-bistri.fluoromethyloxetano-(3',4';16a,17a)-6,9a-

difluoro-l 15-hydroxy-21-aeetoxypregna-1,4,6,-

triene-3,20-dione.

Example 1 1 A suspension of 1 g. of 2,2'-bistrifluoromethyloxetano(3',4';16a,l7a) hydroxy 21 acetoxypregna-1,4- diene-3,20-dione in 60 ml.of methanol is treated with a solution of 1 g. of potassium carbonate in6 ml. of water. The mixture is heated at reflux for one hour, cooled inice and diluted with water. The solid which forms is collected byfiltration, washed with water and dried ,to yield2,2-bistrifluoromethyloxetano(3',4';16a,17a) 115,21dihydroxypregna-1,4-diene-3,20-dione which is recrystallized fromacetone2hexane.

Utilizing the same procedure, other 21-acetoxy compounds of the presentinvention are converted to the corresponding 21-hydroxy compounds.Notably among these are the following:

What is claimed is: 1. A compound according to the formula:

wherein R is hydrogen, chloro, fluoro, or methyl;

R is hydrogen or methyl;

R is keto or the group in which R is hydrogen, tetrahydropyran-Z-yl,tetrahydrofuran-Z-yl, or a hydrocarbon carboxylic acyl group of lessthan 12 carbon atoms, R being keto when Z is a carbon-carbon doublebond;

each of Z and Z is a carbon-carbon single bond or a carbon-carbon doublebond, Z being a carbon-carbon single bond when R is hydrogen.

2. A compound according to claim 1 wherein R is hydrogen ore-methyl; Ris methyl; R is keto; each of Z and Z is a. carbon-carbon single bond.

3. A'compound according to claim 1 wherein R is hydrogen or it-methyl; Ris methyl; R is keto; Z is a carbon-carbon single bond; Z is acarbon-carbon double bond. T

4. A compound according to claim 1 wherein R is chloro; R is methyl; Ris keto; Z is a carbon-carbon double bond; Z is a carbon-carbon singlebond.

5. A compound according to claim 1 wherein R is chloro; R is methyl; Ris keto; each of Z and Z is a carbon-carbon double bond.

6. A compound according to claim 1 wherein R is chloro; R is hydrogen; Ris keto; Z is a carbon-carbon double bond; Z is a carbon-carbon singlebond.

' 7. A compound according to the formula:

CHaO R A ii? $3,3 3,,

R is hydrogen, phosphono, tetrahydropyran-Z-yl, tetrahydrofuran-Z-yl, ora hydrocarbon carboxylic acyl group containing less than 12 carbonatoms;

R is hydrogen or fiuoro;

each of Z and Z is a carbon-carbon single bond or a carbon-carbon doublebond.

8. A compound according to claim 7 wherein R is hydrogen or a-methyl; Ris keto; R is hydrogen or acetyl; R is hydrogen; Z is a carbon-carbonsingle bond; Z is a carbon-carbon single bond or a carbon'carbon doublebond.

9. A compound according to claim 7 wherein R is hydrogen or a-methyl; Ris keto; R is hydrogen or acetyl; R is fluoro; Z is a carbon-carbonsingle bond; Z is a carbon-carbon single bond or a carbon-carbon doublebond.

10. A compound according to claim 7 wherein R is a-fluoro; R is keto; Ris hydrogen or acetyl; R is hydrogen; Z is a carbon-carbon single bond;Z is a carbon-carbon single bond or a carbon-carbon double bond.

11. A compound according to claim 7 wherein R is fluoro; R is keto; R ishydrogen or acetyl; R is m-fluoro; Z is a carbon-carbon single bond; Zis a carbon-carbon single bond or a carbon-carbon double bond.

12. A compound according to claim 7 wherein R is methyl; R is keto; R ishydrogen or acetyl; R is hydrogen; Z is a carbon-carbon double bond; Zis a carbon-carbon single bond or a carbon-carbon double bond.

13. A compound according to claim 7 wherein R is methyl; R is keto; R ishydrogen or acetyl; R is fluoro', Z is a carbon-carbon double bond; Z isa carbon-carbon single bond or a carbon-carbon double bond.

14. A compound according to claim 1 wherein R is hydrogen or methyl; Ris methyl; R is keto; Z is a carbon-carbon double bond; Z is acarbon-carbon single bond.

15. A compound according to claim 1 wherein R is hydrogen or methyl; Ris methyl; R is keto; each of Z and Z is a carbon-carbon double bond.

References Cited Pike, 1, B, Journal of Organic Chemistry, vol. 29,1964, pps. 3476-3481.

LEWIS GOTTS, Primary Examiner.

E. G. LOVE, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3,377,343 April 9, 1968 John H. Fried It is certified that error appears inthe above identified patent and that said Letters Patent are herebycorrected as 4 shown below:

Column 1 lines 17 to 27 the left-hand portion ef the formula shouldappear as shown below;

same column 1 lines 28 to 40 the left-hand portion of the formula shouldappear as shown below;

Column 4 line 20 after '0 5" insert g Column 5 line 67,"-Zlacetoxypregnashould read 2lacetoxypregnline 74 and column 6 lines 1and 3 Zl-acetoxypregnaf' each occurrence, should read -2lacetoxypregn-Column 7, line 16, "hydropy" should read hydroxy line 71,"bistrifluoromethyloxentano" should read bistrifluoromethyloxetano-Column 8, line 56, "6o" should read 6u,9a

- line 63 "Z,2bistrifluoromethyloxetano" should read 2 ,2bistrifluoromethyloxetano Column 9 line 2 "headed" should read heatedline 33 "of" should read to Column 11, lines 31 to 40, the portion ofthe formula reading should read Signed and sealed this 3rd day of March1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting OfficerCommissioner of Patents

1. A COMPOUND ACCORDING TO THE FORMULA:
 7. A COMPOUND ACCORDING TO THEFORMULA: